Human Leukocyte Antigen-identical Sibling Donor Research Articles

Análise da rejeição nos pacientes transplantados por anemia aplástica severa condicionados com ciclofosfamida ou a associação desta ao bussulfano

Bone marrow transplantation is an effective therapy for severe aplastic anemia and is generally considered the preferable treatment for young patients who have an HLA (Human Leukocyte Antigen) identical sibling donor. Recent studies report 55% to 80% extended survival. Graft failure owing to rejection or others causes remains an important life-threatening complication following allogeneic bone marrow transplantation for aplastic anemia. It occurs in 55% to 60% of patients receiving HLA identical transplants, using different immunosuppressive therapies before and after transplant. The BMT Unit of Federal University of Parana had 178 cases of SAA transplants from 1993 to 2001 using either cyclophosphamide (CY) alone or associated with busulfan (CY+BU) for conditioning regimen. Graft failure occurred in 39 of the cases. Among patients conditioned with CY, 24 (46%) presented graft failure, of whom 3 (6%) suffered primary graft failures and 21 (40%) transient engraftment. Among patients conditioned with BU+CY, 15 (12%) suffered graft failure, 4 (3%) primary graft failures and 11 (9%) transient engraftment. The patients conditioned with CY and experienced rejection had a survival of around 80%, because they underwent another transplantation or due to immunosuppressive treatment with cyclosporin A. The patients conditioned with BU+CY who suffered rejections had a survival of approximately 35%.

Significance of a Single Human Leukocyte Antigen Mismatch on the Outcome of Nonmyeloablative Allogeneic Stem Cell Transplantation from Related Donors Using the Mexican Schedule.

The Mexican approach was used to conduct nonmyeloablative stem cell transplantation (SCT) in patients with various malignant and non-malignant hematologic diseases. Patients received a modified, low-intensity conditioning regimen, which included oral busulphan 4 mg/kg on Days −6 and −5, IV cyclophosphamide 350 mg/m2 on Days −4, −3, and −2, IV fludarabine 30 mg/m2 on Days −4, −3, and −2, oral cyclosporine A 5 mg/kg twice daily staring on Day −1 (continuing until Day 180), and IV methotrexate 5 mg/m2 on Days +1, +3, +5, and +11. Allografts were prospectively performed in 58 patients using sibling donors that were either human leukocyte antigen (HLA) identical (6/6) or compatible with 1 mismatch (5/6). In allografts where the donor was an HLA identical sibling (n = 40), the median overall survival was 33 months compared to 8 months when the donor was an HLA compatible sibling (n = 18; P <.01). The 52-month survival was 47% versus 38% in patients receiving allografts from HLA-identical donors and HLA-compatible donors, respectively. The prevalence of acute graft-versus-host-disease (GVHD) was 57% versus 38%, the prevalence of chronic GVHD was 25% versus 11%, and the relapse rate was 45% versus 55% in patients receiving allografts from HLA-identical donors and HLA-compatible donors, respectively. Two patients failed to engraft; both were 5/6 matches. Despite a trend toward less favorable results in patients allografted from HLA compatible (5/6) siblings, most differences in outcome were not significant, likely due to the small number of patients in the study. These data suggest that nonmyeloablative SCT using the Mexican approach may be a valid option for individuals with either an HLA identical or HLA compatible sibling donor.

Higher Mortality After Allogeneic Peripheral-Blood Transplantation Compared With Bone Marrow in Children and Adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry

Peripheral-blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Despite lack of data on PBSC transplantation in children, there has been a change in clinical practice, with increasing numbers of children receiving PBSC allografts. We compared the results of 143 PBSC and 630 BM transplants from human leukocyte antigen-identical sibling donors in children aged 8 to 20 years with acute leukemia. PBSC transplant recipients were older, and were more likely to have advanced leukemia, receive growth factors post-transplantation, and have undergone transplantation more recently. Risks of acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, treatment failure (relapse or death), and overall mortality were compared using Cox proportional hazards regression to adjust for potentially confounding factors. Hematopoietic recovery was faster after PBSC transplantation. Risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSC transplantation (relative risk [RR], 1.85; 95% CI, 1.28 to 2.66; P = .001). In contrast to reports in adults, treatment-related mortality (RR, 1.89; 95% CI, 1.28 to 2.80; P = .001), treatment failure (RR, 1.31; 95% CI, 1.03 to 1.68; P = .03), and mortality (RR, 1.38; 95% CI, 1.07 to 1.79; P = .01) were higher after PBSC transplantation. Risks of relapse were similar. These data suggest poorer outcomes after PBSC compared with BM transplantation in children after adjusting for relevant risk factors. Given the trend toward increased use of PBSC allografts in children, prospective clinical trials are required to determine their appropriate role in this group of patients.

Allogeneic Peripheral Blood Versus Bone Marrow Transplantation: Children Are Small Adults and More

This issue of the Journal of Clinical Oncology reports the controversial findings of the International Bone Marrow Transplant Registry retrospective review comparing allogeneic stem-cell sources— bone marrow (BM) versus granulocyte colony-stimulating factor (G-CSF) –mobilized peripheral-blood stem cells (PBSC)—in children and adolescents. In their review of 143 PBSC and 630 BM human leukocyte antigen–identical sibling donor transplants in children with leukemia aged 8 to 20 years, Eapen et al found a higher rate of chronic graft-versus-host disease (GVHD) and treatment-related mortality (with similar relapse risk) in children receiving PBSC compared with BM. Overall, there was poorer survival when PBSC were used as the donor source, even after adjusting for relative risks. This is an unsettling finding, given that in 2003, close to 30% of pediatric matched sibling transplants reported to the International Bone Marrow Transplant Registry used PBSC as the donor source. The shift in clinical practice from using BM to G-CSF– mobilized PBSC as the hematopoietic progenitor cell source has arguably been among the most rapid and sweeping changes in clinical hematopoietic allogeneic transplantation this decade, second only to changes in the management of chronic myelogenous leukemia after the introduction of imatinib. Since it is common practice in pediatrics to extrapolate from adult therapy, the transition has occurred in both pediatrics and adult transplantation. In general, this is a reasonable approach, especially if there are no clear developmental or physiologic reasons to expect differences in efficacy or toxicity between children and adults. The biologic differences between the two stem-cell products include differences in both intermediate hematopoietic progenitors and T cells. In multiple animal and human trials, there has consistently been a strong correlation between the number of T cells in the transplanted graft and development of GVHD. The 10-fold increase in T cells in a PBSC graft initially made allogeneic transplant physicians hesitant to use PBSC as a stem-cell product, but experience has shown that PBSC can be safely used as an allogeneic stem-cell source. In the process of mobilization, the T cells have been exposed to G-CSF, which is known to modify T-cell responses in the direction of the T-helper-2 response, potentially explaining the tolerable GVHD observed. Early, predominately adult, experience with PBSC, frequently in patients with advanced malignancies, demonstrated more rapid count recovery and less early transplantrelated mortality (TRM), which translated into improved survival. As reviewed in the article by Eapen et al, subsequent results of randomized trials have been mixed. The overall conclusion is that PBSC transplantation outcomes are at least equivalent to, if not better than, BM as an allogeneic stem-cell source. Hence, there has been a rapid transition in clinical practice to the use of G-CSF–mobilized PBSC as the allogeneic donor source, with the rationale that more rapid postcollection recovery of the donor and more rapid post-transplantation recovery of hematopoiesis (with resultant shortening of hospital stay and decreased early transplant-related mortality in patients, especially those with advanced disease or poor performance status at the time of transplantation) were all important outcome goals, even if survivals was equivalent. The transition of clinical practice to use of G-CSF– mobilized PBSC has been slower in pediatrics, partially due to concerns of donor safety since donors are often minors. With increased experience in young child apheresis, there has been a growing acceptance that even young children can safely receive G-CSF and undergo apheresis, as recently reviewed by the Pediatric Blood and Marrow Transplant Consortium. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 24 DECEMBER 15 2004

Reduced risk for extensive chronic graft-versus-host disease in patients receiving transplants with human leukocyte antigen-identical sibling donors given polymerase chain reaction-based preemptive therapy against cytomegalovirus.

The aim of this study was to investigate the relationship between cytomegalovirus (CMV) and extensive chronic graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation (SCT). Two hundred sixty-two consecutive patients undergoing conventional SCT with human leukocyte antigen-identical sibling donors, given cyclosporine A and methotrexate as GvHD prophylaxis and surviving more than 3 months after SCT, were retrospectively analyzed. Most patients received transplants because of a hematologic malignancy (n=226), but 36 patients with nonmalignant disorders were included in the analysis. Ninety-nine patients were monitored for CMV infection with rapid virus isolation and 163 patients by either a pp65 antigenemia test (n=5) or a qualitative polymerase chain reaction (PCR) assay for CMV-DNA (n=158). One hundred thirty (50%) of the patients developed chronic GvHD, of whom 17 (6.5%) developed extensive chronic GvHD. Risk factors for development of extensive chronic GvHD were determined by multivariate logistic regression. The strategy of PCR-based monitoring for CMV-DNA, giving preemptive antiviral therapy on demand, significantly decreased the risk for developing extensive chronic GvHD (odds ratio=0.32, P =0.03). No other factors tested, including recipient and donor age and sex, source of graft, cell dose, and acute GvHD, had any significant effect on the development of extensive chronic GvHD. We conclude that the risk for extensive chronic GvHD in this homogenous group of patients was reduced by the use of PCR-based preemptive therapy.

Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

To determine the results of allogeneic hematopoietic stem cell (HSC) transplantation for chronic myelogenous leukemia (CML) at various stages of the disease in children, a retrospective analysis was carried out on the outcome of transplants performed on 76 children and teenagers with CML between 1982 and 1998. In all, 60 patients were transplanted from a matched sibling donor (MSD) and 16 from a matched unrelated donor (MUD). There was a higher incidence of acute graft-versus-host disease after MUD transplantation (P<10(-3)). The main cause of death was transplant-related toxicity in both groups. In MSD recipients, the probability of relapse at 5 years for patients transplanted in the first chronic phase was lower than in patients transplanted in the advanced phase (relative risk (rr)=5.90; 95% confidence interval (CI), 1.85-18.82, P<0.01). The estimated 5-year event-free survival (EFS) rate was higher after MSD vs MUD transplantation (61% (95% CI, 48-73%) vs 27% (95% CI, 4-49%), rr=0.25, P<10(-3)). In children transplanted from MSD, the 5-year EFS was higher when transplantation was performed in the first chronic phase vs the advanced phases (73% (95% CI, 59-87%) vs 32% (95% CI, 10-54%), P<10(-3)). Disease status at transplantation was the unique factor influencing survival in patients undergoing transplantation from MSD with a better outcome for those transplanted in the first chronic phase. Allogeneic HSC offers a possibility of curing childhood CML with a significant advantage for patients transplanted in chronic phase using a human leukocyte antigen-identical sibling donor.

Comparisons Between Allogeneic Peripheral Blood Stem Cell Transplantation and Allogeneic Bone Marrow Transplantation in Adult Hematologic Disease: A Single Center Experience

This retrospective study compared the outcomes in 32 adult patients with hematologic diseases (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, severe aplastic anemia) who received allogeneic bone marrow transplantation (BMT, n = 14; median age, 28 years) or allogeneic peripheral blood stem cell transplantation (PBSCT, n = 18; median age, 29 years) from human leukocyte antigen-identical sibling donors. Median follow-up was 58 months in BMT recipients and 18 months in PBSCT recipients. Neutrophil (median, Day 8 vs Day 13, p < 0.001) and platelet engraftment (median, Day 9 vs Day 17, p < 0.001) was faster in the PBSCT group than in the BMT group. Patients receiving PBSCT required less platelet transfusion than those receiving BMT (median, 54 units vs 144 units, p < 0.001), but there was no significant difference in red cell transfusion. At 100 days, there was no difference in the incidence of acute graft-versus-host disease (GVHD) (42.9% vs 33.3%, p = 0.72) or grade II-IV acute GVHD (14.3% vs 5.6%, p = 0.57), and there was no difference in the cumulative incidence of chronic GVHD (20% vs 33.3%, p = 0.67). No chronic GVHD was noted in any relapsed patients (BMT, 5; PBSCT, 3), and no patients with chronic GVHD during follow-up had a relapse. Relapse was the most frequent cause of death inboth groups (BMT, 5/9, 55.6%; PBSCT, 3/4, 75%; p = 0.25); all relapses occurred within 1 year after transplantation. Overall survival was significantly better in the PBSCT group (35.7% vs 77.8%, p = 0.029), but this difference was lost if only hematologic malignancies were analyzed (30.8% vs 63.6%, p = 0.20). Our results are similar to those reported previously, with faster neutrophil and platelet engraftment and less severe acute GVHD and extensive chronic GVHD with PBSCT. Allogeneic PBSCT is a feasible and beneficial alternative to allogeneic BMT in adult hematologic disease.

Influence of One Human Leukocyte Antigen Mismatch on Outcome of Allogeneic Bone Marrow Transplantation from Related Donors

This study compares the clinical outcomes of 60 consecutive patients who received an allogeneic blood or marrow stem cell transplant (BMT) from one Human Leukocyte Antigen (HLA) mismatched related donors with those of 120 matched patients who had HLA identical sibling donors. The control patients were matched for diagnosis, disease status, conditioning regimen, and age at BMT. All patients received standard CYA and MTX for GVHD prophylaxis. The probability of overall survival (OS) at 5 years was 35% in the study group compared to 56% in the control group. The relapse rates and acute GVHD rates did not differ between the two groups. Graft failure was a significant problem in the study group compared to the control group (13 vs. 0%, p<0.0001). All cases of graft failure occurred in patients with a mismatch in the host-versus-graft direction. BMT-related deaths were also increased in the study group. Forty percent of deaths were caused by infection in the study group vs. 19% in the control group (p<0.01). In conclusion, the OS of patients receiving marrow/stem cells from one antigen mismatched related donors was inferior to that of controls with HLA-identical related donors. There was an increase in mortality related to infections occurring in the setting of an increased frequency of graft failure in these patients.

Results of Bone Marrow Transplants from Human Leukocyte Antigen-Identical Sibling Donors for Treatment of Childhood Leukemias

Bone marrow transplantation is an effective treatment for leukemia. Cures are possible in 20-80% of transplant recipients depending on the stage of leukemia at the time of transplant. The antileukemia efficacy of transplants result from high-dose chemotherapy and/or radiation given pretransplant and from immune-mediated effects of the graft. Success of the procedure is limited by transplant-related complications, including graft rejection, graft-vs.-host disease and interstitial pneumonia. Five-year leukemia-free survival ranges from approximately 25% for children transplanted with advanced leukemia, to > 60% in those transplanted in first remission of acute leukemia or first chronic phase of chronic myeloid leukemia. Candidates for transplant include children failing conventional therapy and, possibly, those with early leukemia characterized by features predicting a poor response to conventional therapy.